Charcot-Marie-Tooth (CMT) neuropathy, also known as hereditary motor and sensory neuropathy, is a heterogeneous group of inherited diseases of peripheral nerves. CMT is a common disorder affecting both children and adults. CMT causes significant neuromuscular impairment. It is estimated that 1/2500 persons have a form of CMT, making it one of the largest categories of genetic diseases.
CMT comprises a frequently occurring, genetically heterogeneous group of peripheral neuropathies, although the clinical picture is rather uniform. See, Vance et al., The many faces of Charcot-Marie-Tooth disease. Arch Neurol 57, 638-640 (2000). Following electrophysiological criteria, CMT falls into two major forms, the demyelinating CMT type 1 with decreased nerve conduction velocities (NCV), and the axonal form, CMT type 2. In contrast to the well known molecular genetic defects causing the CMT1 phenotype, several genes underlying CMT2 have only recently been identified. So far, seven loci for autosomal dominant CMT2 have been assigned to chromosomes 1p35-36 (CMT2A), 3q13-22 (CMT2B), 12q23-24 (CMT2C), 7p14 (CMT2D), 8p21 (CMT2E), 7q11-21 (CMT2F), and 12q12-13.3 (CMT2G). See, e.g., Ben Othmane et al., Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 17, 370-375 (1993); Kwon et al., Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am J Hum Genet 57, 853-858 (1995); Klein et al., The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders. Neurology 60, 1151-1156 (2003); Ionasescu et al., Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Hum Mol Genet 5, 1373-1375 (1996); Mersiyanova et al., A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet 67, 37-46 (2000); Ismailov et al., A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. Eur J Hum Genet 9, 646-650 (2001).
Currently four genes, involved in CMT2A, CMT2B, CMT2D and CMT2E, have been identified. The neurofilament-light gene (NEFL) is responsible for CMT2E, and a large study revealed that NEFL mutations occur in only 2% of CMT patients. See, Jordanova et al., Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease, Brain 126, 590-597 (2003). Two missense mutations in the RAS-related late-endosomal GTP-binding protein RAB7 have been shown to cause CMT2B in 3 extended families and 2 familial cases with different ethnic backgrounds. See, Verhoeven et al., Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet 72, 722-727 (2003). Missense mutations in the gene coding for Glycyl tRNA synthetase (GARS) were reported to cause CMT2D and distal hereditary motor neuropathy type VII in different families. Antonellis et al., Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V. Am J Hum Genet 72, 1293-1299 (2003).
In a single Japanese family with a posterior probability supporting linkage to the CMT2A locus, a missense mutation in the KIF1B-β gene (c.293A>T; Gln98Leu) was found to co-segregate with the disease. Zhao et al., Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bb. Cell 105, 587-597 (2001). The Leu98 allele was not found in 95 healthy control individuals. In addition, the authors of this study demonstrated that Kif1B+/− mice developed a chronic peripheral neuropathy resembling the CMT phenotype in humans. Zhao et al. 2001. Yet, no further CMT2A families have been reported with a mutation in KIF1B-β. Therefore, it may be desirable to find a different method of diagnosing Charcot-Marie-Tooth disease.